Cancer cachexia, a wasting syndrome characterized by the dramatic loss of skeletal muscle and adipose tissue, is perhaps the most poorly understood feature of cancer pathophysiology. Despite its major impact on patient morbidity and mortality, an understanding of the underlying mechanisms is quite primitive. While rodent tumor graft models have spurred existing insight, common principles of tumor signaling and host response remain obscure, and this void has limited development of effective therapies. In the face of such confusion, Drosophila can serve as a reductionist yet powerful alternative model. Malignant overgrowths that share features of human cancer can be readily created via Drosophila genetics, and the fly has a track record of contributions directly relevant to cancer biology. We have discovered that fly tumors introduced into wild-type hosts can induce a dramatic wasting-like response in peripheral host tissues, including loss of tissue mass with altered trophic signaling. The specific aim of this application is to identify the underlying mechanisms, with the goal of discovering common principles with human cancer cachexia and advancing insight into tumor-host tissue interactions in general. We will first capitalize on the rich understanding of Drosophila signaling biology (including functional necessity/sufficiency assays) to determine the pathways inducing wasting response in host tissues. We will next test both inflammation and altered nutrient signaling-based models for wasting. We will then uncover or rule out tumor-produced signals as instigators of host tissue wasting, leveraging unpublished transcriptome datasets from tumors that can and cannot induce wasting. Finally, we will investigate the applicability of the mechanisms uncovered in Drosophila to mammalian cachexia models. This proposal represents the first investigation of cachexia in a non-mammalian system, with all the experimental power that the flagship model genetic organism can bring. Despite the many differences between flies and humans and their cancers, this high-risk/high-gain project has strong potential to uncover fundamental and conserved pathways of tissue wasting, which could bring clarity to current confusion in the field and generate new directions for investigation.